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Trastuzumab, a monoclonal antibody that is selective for cells that overexpress the erbB2 receptor protein tyrosine kinase, is a promising targeted therapy for the treatment of breast cancer. Surprisingly, toxic cardiovascular side effects were discovered in late-phase clinical trials, and these effects were most prominent when trastuzumab was combined with anthracycline chemotherapy. We review recent data focusing on how erbB2 monoclonal antibodies could exert a cardiotoxic effect through unique cardiomyocyte cell surface and intracellular structural features, and how an individual's cardiac susceptibility to erbB2 monoclonal antibodies may be dictated by the ability of erbB2 monoclonal antibodies to bind cardiomyocytes. In addition, we discuss ways that anthracyclines may also affect erbB2/erbB4/neuregulin receptor signaling, explaining the apparent synergistic effect. Further investigation of the role of normal …